Cisplatin (diamminedichloroplatinum) is currently a standard therapy for testicular and ovarian tumors despite its renal toxicity. Since the toxicity is dose-related, the use of increased doses against other human cancers is restricted.
Research efforts have been directed to finding cisplatin analogs of reduced toxicity while remaining effective as anti-cancer agents. To date, however, no other platinum compound has been approved for general clinical use.
Research efforts have also been directed to finding metal chelating agents which when administered with cisplatin exhibit a renal-sparing effect. The most successful of these chelators is diethyldithiocarbamate (DDTC). See Borch et al. Proc. Natl. Acad. Sci. U.S.A. (1979) 76:6611-6614; and Walker et al., Annals Clin. & Lab. Sci. (1981) Vol. II, pp. 397-410. Recently it has been reported that certain hydroxylated dithiocarbamates such as dihydroxyethyl dithiocarbamate may provide an improvement over DDTC in reducing nephrotoxicity. Juckett et al., Am. Assoc. Canc. Res. Proc. (1984) 25:322 (ABST 1274); and (1985) 373 (ABST. 1472).
The original experiments of Borch et al. (1979, cited above) utilized post-administration of DDTC, the dithiocarbamate inhibitor being given from 1 to 4 hours after the start of the administration of the cisplatin. Proc. Natl. Acad. Sci. U.S.A. (1980) 77:5441-5444.
A more extensive study of administration times for DDTC was carried out by Gale et al., Annals Clin & Lab. Sci. (1982) 12:345-355. These researchers tested DDTC administration 30 minutes before cisplatin administration, and 30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after the start of administration. They concluded: "When DDTC was given 0.5 hours prior to cisplatin, there was excellent protection from the toxic effects of cisplatin. Optimum therapeutic efficiency was obtained when DDTC was given 1 to 2 hours after cisplatin." Juckett et al. (1984 and 1985, cited above) administered the dithiocarbamates around the time of cisplatin infusion, the earliest time being 30 minutes prior.
As far as is known, no administration protocol has been described for any dithiocarbamate chelator which entirely suppresses an effect on renal function, as measured by blood urea nitrogen (BUN) and creatinine values. In prior art methods, BUN values remained substantially elevated despite the co-administration of a dithiocarbamate chelator. There has been a recognized need to provide more effective renal sparing to permit cisplatin to be administered in larger doses, and/or used for a wider range of cancer therapy